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Thromb Haemost 2007; 98(01): 131-137
DOI: 10.1160/TH06-11-0625
Review Article
Schattauer GmbH

Clinical implications of gene polymorphisms in venous leg ulcer: A model in tissue injury and reparative process

Paolo Zamboni
1   Vascular Disease Center, Center Study Haemostasis and Thrombosis, University of Ferrara, Ferrara, Italy
,
Donato Gemmati
1   Vascular Disease Center, Center Study Haemostasis and Thrombosis, University of Ferrara, Ferrara, Italy
› Author Affiliations Financial support:Research supported by the Italian Ministry for the University and the Scientific Research and by the Foundation Cassa di Risparmio di Ferrara.
Further Information

Publication History

Received 04 November 2007

Accepted 27 April 2007

Publication Date:
29 November 2017 (online)

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Summary

Wound healing is a multi-step process involving complex pathways at cell and molecular level. Lack of understanding of the molecular mechanisms and pathogenesis of impaired healing in chronic leg ulcers limits clinical assessment and management. In addition, individual genetic background certainly affects the response to treatment and specifically modulates the unfavourable lesion environment.Although the number of actors involved in the aetiology of chronic wounds is extremely high, the ability to find out groups of candidate genes on the basis of clinical and physio-pathological findings is a crucial step.The present review demonstrates how recognition of functional gene variants, mostly single nucleotide polymorphisms (SNPs), significantly involved in wound healing and venous ulcer establishment, extra- ordinarily helps prognosis, diagnosis and treatment of chronic wounds.We deal with on how one can manage SNPs in coagulation factor XIII (FXIII) and hemochromatosis (HFE) genes as molecular markers or prognostic tools. In this fashion, we could pave the way for strategies aimed to single out in advance categories of patients at increased risk to develop severe complications of chronic venous disorders, or to predict the healing time after surgical intervention. Because of its relevant epidemiology and its easily visualized lesions, venous leg ulcer is an ideal model for investigating, the mechanisms of tissue injury and reparative process,as well as the influence of different genetic backgrounds.

Keywords

Wound healing - single nucleotide polymorphisms - oxidative - stress - inflammation - factor XIII - iron
 

  • References

  • 1 Riedel K, Riedel F, Goessler UR. et al. Current status of genetic modulation of growth factors in wound repair. Int J Mol Med 2006; 17: 183-193.
    PubMedGoogle Scholar
  • 2 Broughton G, 2nd Janis JE, Attinger CE. Wound healing: an overview. Plast Reconstr Surg 2006; 117 (Suppl. 07) 1e-S-32e-S.
    PubMedGoogle Scholar
  • 3 Abbade LP, Lastoria S. Venous ulcer: epidemiology, physiopathology, diagnosis and treatment. Int J Dermatol 2005; 44: 449-456.
    CrossrefPubMedGoogle Scholar
  • 4 Gohel MS, Taylor M, Earnshaw JJ. et al. Risk factors for delayed healing and recurrence of chronic venousleg ulcers—an analysis of 1324 legs. Eur J Vasc Endovasc Surg 2005; 29: 74-77.
    CrossrefPubMedGoogle Scholar
  • 5 Margolis DJ, Berlin JA, Strom BL. Riskfactors associated with the failure of avenous ulcer to heal. Arch Dermatol 1999; 135: 920-926.
    PubMedGoogle Scholar
  • 6 Ashworth JJ, Smyth JV, Pendleton N. et al. The dinucleotide (CA) repeat polymorphism of estrogen receptor beta but not the dinucleotide (TA) repeat polymorphism of estrogen receptor alpha is associated with venousul ceration. J Steroid Biochem Mol Biol 2005; 97: 266-270.
    CrossrefPubMedGoogle Scholar
  • 7 Nagy N, Szolnoky G, Szabad G. et al. Single nucleotide polymorphisms of the fibroblast growth factor receptor 2 gene in patients with chronic venous insufficiency with leg ulcer. J Invest Dermatol 2005; 124: 1085-1088.
    CrossrefPubMedGoogle Scholar
  • 8 Wallace HJ, Vandongen YK, Stacey MC. Tumornecrosis factor-alpha gene polymorphism associated with increased susceptibility to venous leg ulceration. J Invest Dermatol 2006; 126: 921-925.
    PubMedGoogle Scholar
  • 9 Gemmati D, Tognazzo S, Serino ML. et al. Factor XIII V34L polymorphism modulates the risk of chronic venous leg ulcer progression and extension. Wound Repair Regen 2004; 12: 512-517.
    CrossrefPubMedGoogle Scholar
  • 10 Zamboni P, Tognazzo S, Izzo M. et al. Hemochromatos is C282Y gene mutation increases the risk of venous leg ulceration. J Vasc Surg 2005; 42: 309-314.
    CrossrefPubMedGoogle Scholar
  • 11 Gemmati D, Tognazzo S, Catozzi L. et al. Influence of gene polymorphisms in ulcer healing process after superficial venous surgery. J Vasc Surg 2006; 44: 554-562.
    CrossrefPubMedGoogle Scholar
  • 12 Tognazzo S, Gemmati D, Palazzo A. et al. Prognostic role of factor XIII gene variants in nonhealing venous leg ulcers. J Vasc Surg 2006; 44: 815-819.
    CrossrefPubMedGoogle Scholar
  • 13 Ichinose A. Physiopathology and regulation of factor XIII. Thromb Haemost 2001; 86: 57-65.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Muszbek L, Yee VC, Hevessy Z. Blood coagulation factor XIII. Structure and function. Thromb Res 1999; 94: 271-305.
    CrossrefPubMedGoogle Scholar
  • 15 Vanscheidt W, Hasler K, Wokalek H. et al Factor XIII-deficiency in the blood of venous leg ulcer patients. Acta Derm Venereol 1991; 71: 55-57.
    PubMedGoogle Scholar
  • 16 Wozniak G, Noll T, Brunner U. et al. Topical treatment of venous ulcer with fibrin stabilizing factor: Experimental investigation of effects on vascular permeability. Vasa 1999; 28: 160-163.
    CrossrefPubMedGoogle Scholar
  • 17 Herouy Y, Hellstern MO, Vanscheidt W. et al. Factor XIII-mediated inhibition of fibrinolysis and venous leg ulcers. Lancet 2000; 355: 1970-1971.
    CrossrefPubMedGoogle Scholar
  • 18 Hildenbrand T, Idzko M, Panther E. et al. Treatment of nonhealing leg ulcers with fibrin-stabilizing factor XIII: a case report. Dermatol Surg 2002; 28: 1098-1099.
    PubMedGoogle Scholar
  • 19 Zelikovski A, Podlipski A, Sternberg A. et al. Changes in chemical, hematological and blood gases values in chronic venous insufficiency of the lower limbs. Vasa 1977; 6: 26-30.
    PubMedGoogle Scholar
  • 20 Yeoh-Ellerton S, Stacey MC. Iron and 8-isoprostane levels in acute and chronic wounds. J Invest Dermatol 2003; 121: 918-925.
    CrossrefPubMedGoogle Scholar
  • 21 Zamboni P, Izzo M, Tognazzo S. et al. The overlapping of local iron overload and HFE mutation invenous leg ulcer pathogenesis. Free Radic Biol Med 2006; 40: 1869-1873.
    CrossrefPubMedGoogle Scholar
  • 22 Bergan JJ, Schmid-Schonbein GW, Smith PD. et al. Chronic venous disease. N Engl J Med 2006; 355: 488-498.
    CrossrefPubMedGoogle Scholar
  • 23 Callam MJ, Ruckley CV, Harper DR. et al. Chronic ulceration of the leg: extent of the problem and provision of care. Br Med J 1985; 290: 1855-1856.
    CrossrefPubMedGoogle Scholar
  • 24 Nelzen O, Bergqvist D, Lindhagen A. Theprevalence of chronic lower-limb ulceration has been under-stimated: results of a validated population questionnaire. Br J Surg 1993; 83: 255-258.
    PubMedGoogle Scholar
  • 25 Eberth-Willershausen W, Marshall M. Prevalence, risk factors and complications of peripheral venous diseases in the Munich population. Hautarzt 1984; 35: 68-77.
    PubMedGoogle Scholar
  • 26 Ruckley CV, Evans CJ, Allan PL. et al. Chronic venous insufficiency: clinical and duplex correlations. The Edinburgh Vein Study of venous disorders in the general population. J Vasc Surg 2002; 36: 520-525.
    CrossrefPubMedGoogle Scholar
  • 27 Heit JA, Rooke TW, Silverstein MD. et al. Trends in the incidence of venous stasissyndrome and venous ulcer: a 25-year population-based study. J Vasc Surg 2001; 33: 1022-1027.
    CrossrefPubMedGoogle Scholar
  • 28 Nicolaides AN. Theinternational consensus group. The investigation of chronic venous insufficiency. A Consensus Statement. Circulation 2000; 102: 126-163.
    CrossrefPubMedGoogle Scholar
  • 29 Coleridge Smith PD, Thomas P, Scurr JH. et al. Causes of venous ulceration: a new hypothesis. Br Med J 1988; 296: 1726-1727.
    CrossrefPubMedGoogle Scholar
  • 30 Zamboni P, Izzo M, Fogato L. et al. Urine haemosiderin: a novel marker to assess the severity of chronic venous disease. J Vasc Surg 2003; 37: 132-136.
    CrossrefPubMedGoogle Scholar
  • 31 Browse NL, Burnand KG. The cause of venous ulceration. Lancet 1982; 2: 243-245.
    PubMedGoogle Scholar
  • 32 Joshi A, Sloan P. Role of “fibrin” cuffs in chronic nonspecific oral ulceration. Wound Repair Regen 2004; 12: 18-23.
    CrossrefPubMedGoogle Scholar
  • 33 Distante S. Genetic predisposition to iron overload: prevalence and phenotypic expression of hemochromatosis-associated HFE-C282Y gene mutation. Scand J Clin Lab Invest 2006; 66: 83-100.
    CrossrefPubMedGoogle Scholar
  • 34 Beutler E, Felitti VJ, Koziol JA. et al. Penetrance of C282Y hereditary haemochromatosis mutation in USA. Lancet 2002; 359: 211-218.
    CrossrefPubMedGoogle Scholar
  • 35 McCune CA, Ravine D, Worwood M. et al. Screening for hereditary haemochromatosis within families and beyond. Lancet 2003; 362: 897-898.
    PubMedGoogle Scholar
  • 36 Zamboni P, Scapoli G, Lanzara V. et al. Serum iron and MMP-9 variations in limbs affected by chronic venous disease and venous leg ulcers. Dermatol Surg 2005; 31: 644-649.
    CrossrefPubMedGoogle Scholar
  • 37 Wenk J, Foitzik A, Achterberg V. et al. Selective pick-up of increased iron by deferoxamine-coupled cellulose abrogates the iron-driven induction of matrix-degrading metalloproteinase 1 and lipid peroxidation in human dermal fibroblasts in vitro: a new dressing concept. J Invest Dermatol 2001; 116: 833-839.
    CrossrefPubMedGoogle Scholar
  • 38 Ackerman Z, Seidenbaum M, Loewenthal E. et al. Overload of iron in the skin of patients with varicose ulcers. Possibile contributing role of iron accumulation in progression of the disease. Arch Dermatol 1988; 124: 1376-1378.
    CrossrefPubMedGoogle Scholar
  • 39 Sullivan JL. Is stored iron safe?. J Lab Clin Med 2004; 144: 280-284.
    CrossrefPubMedGoogle Scholar
  • 40 Wenner A, Leu HJ, Spycher MA. et al. Ultrastructural changes of capillaries in chronic venous insufficiency. Expl Cell Biol 1980; 48: 1-14.
    PubMedGoogle Scholar
  • 41 Zamboni P. The big idea: iron-dependent inflammation in venous disease and proposed parallelsin multiple sclerosis. J R Soc Med 2006; 99: 589-593.
    CrossrefPubMedGoogle Scholar
  • 42 Takase S, Pascarella L, Lerond L. et al. Venous hypertension, inflammation and valve remodeling. Eur J Vasc Endovasc Surg 2004; 28: 484-493.
    CrossrefPubMedGoogle Scholar
  • 43 Wilkinson LS, Bunker C, Edwards JC. et al. Leukocytes: their role in the etiopathogenesis of skin damage in venous disease. J Vasc Surg 1993; 17: 669-675.
    CrossrefPubMedGoogle Scholar
  • 44 Rosner K, Ross C, Karlsmark T. et al. Role of LFA-1/ICAM-1, CLA/E-selectin and VLA-4/VCAM-1 pathways in recruiting leukocytes to the various regions of the chronic leg ulcer. ActaDermVenereol 2001; 81: 334-339.
    PubMedGoogle Scholar
  • 45 Trengove NJ, Stacey MC, Macauley S. et al. Analysis of the acute and chronic wound environments: the role of proteases and their inhibitors. Wound Rep Reg 1999; 7: 442-452.
    CrossrefPubMedGoogle Scholar
  • 46 Palolahti M, Lauharanta J, Stephens RW. et al. Proteolytic activity in leg ulcer exudate. Exp Dermatol 1993; 2: 29-37.
    CrossrefPubMedGoogle Scholar
  • 47 Wysocki AB, Staiano-Coico L, Grinnell F. Wound fluid from chronic leg ulcers contains elevated levels of metalloproteinases MMP-2 and MMP-9. J Invest Dermatol 1993; 101: 64-68.
    CrossrefPubMedGoogle Scholar
  • 48 Bullen EC, Longtaker MT, Updike DL. et al. Tissue inhibitor of metalloproteinases-1 is decreased and activatedgelatinases are increased in chronic wounds. J Invest Dermatol 1995; 104: 236-240.
    CrossrefPubMedGoogle Scholar
  • 49 Weckroth M, Vaheri A, Lauharanta J. et al. Matrix metalloproteinases, gelatinase and collagenase in chronic leg ulcers. J Invest Dermatol 1996; 106: 1119-1124.
    CrossrefPubMedGoogle Scholar
  • 50 Vaalamo M, Weckroth M, Puolakkainen P. et al. Patterns of matrix metalloproteinase and TIMP-1 expression in chronic and normally healing human cutaneous wounds. Br J Dermatol 1996; 135: 52-59.
    CrossrefPubMedGoogle Scholar
  • 51 Vaalamo M, Leivo T, Saarialho-Kere U. Differential expression of tissue inhibitors of metalloproteinases (TIMP-1, -2, -3, and -4) in normal and aberrant wound healing. Hum Pathol 1999; 30: 795-802.
    CrossrefPubMedGoogle Scholar
  • 52 Saito S, Trovato MJ, You R. et al. Role of matrix metalloproteinases 1, 2, and 9and tissue inhibitor of matrix metalloproteinase-1 in chronic venous insufficiency. J Vasc Surg 2001; 34: 930-938.
    CrossrefPubMedGoogle Scholar
  • 53 Herouy Y, Mellios P, Banderir E. et al. Inflammation in stasis dermatitis upregulates MMP-1, MMP-2 and MMP-13 expression. J Dermat Science 2001; 25: 198-205.
    PubMedGoogle Scholar
  • 54 Drakesmith H, Sweetland E, Schimanski L. et al. The hemochromatosis protein HFE inhibits iron export from macrophages. PNAS 2002; 99: 15602-15607.
    CrossrefPubMedGoogle Scholar
  • 55 Moura E, Noordermeer MA, Verhoeven N. et al. Iron release from human monocytes after erythrophagocytosis in vitro: an investigation in normal subjects and hereditary hemochromatosis patients. Blood 1998; 92: 2511-2519.
    PubMedGoogle Scholar
  • 56 Ganz T, Nemeth E. Iron imports. IV. Hepcidin and regulation of body iron metabolism. Am J Physiol Gastrointest Liver Physiol 2006; 290: G199-203.
    CrossrefPubMedGoogle Scholar
  • 57 Nemeth E, Tuttle MS, Powelson J. et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004; 306: 2090-2093.
    CrossrefPubMedGoogle Scholar
  • 58 Harris IR, Yee KC, Walters CE. et al. Cytokine and protease levels in healing and non-healing chronic venous leg ulcers. Exp Dermatol 1995; 4: 342-349.
    CrossrefPubMedGoogle Scholar
  • 59 Gurjar MV, Deleon J, Sharma RV. et al. Role of reactive oxygen species in IL-1 beta-stimulated sustained ERK activation and MMP-9 induction. Am J Physiol Heart Circ Physiol 2001; 281: H2568-2574.
    CrossrefPubMedGoogle Scholar
  • 60 Duckert F, Jung E, Shmerling DH. Ahitherto undescribed congenital haemorrhagic diathesis probably due to fibrin stabilizing factor deficiency. Thromb Diath Haemorrh 1960; 5: 179-186.
    PubMedGoogle Scholar
  • 61 Haanen C. Importance of factor XIII for hemostasis and wound healing. Ned Tijdschr Geneeskd 1972; 116: 448-454.
    PubMedGoogle Scholar
  • 62 Lorand L, Losowsky MS, Miloszewski KJM. Humanfactor XIII: Fibrin-stabilizingfactor. Progr Haemost Thromb 1980; 5: 245-290.
    PubMedGoogle Scholar
  • 63 Miloszewski KJA, Losowsky MS. Fibrin stabilization and factor XIII deficiency. In: Francis JL. Fibrinogen, Fibrin Stabilisation and Fibrinolysis. Chichester Ellis Horwood; 1988: 175-202.
    Google Scholar
  • 64 Peschen M, Thimm C, Weyl A. et al. Possible role of coagulation factor XIII in the pathogenesis of venous leg ulcers. Vasa 1998; 27: 89-93.
    PubMedGoogle Scholar
  • 65 Paye M, Nusgens BV, Lapiere CM. Factor XIII of blood coagulation modulates collagen biosynthesis by fibroblasts in vitro. Haemostasis 1989; 19: 274-283.
    PubMedGoogle Scholar
  • 66 Keski-Oja J, Mosher DF, Vaheri A. Cross-linking of a major fibroblast surface-associated glycoprotein(fibronectin) catalyzed by blood coagulation factor XIII. Cell 1976; 9: 29-35.
    CrossrefPubMedGoogle Scholar
  • 67 Barry EL, Mosher DF. Factor XIII cross-linking of fibronectin at cellular matrix assemblysites. J Biol Chem 1988; 263: 10464-10469.
    PubMedGoogle Scholar
  • 68 Barry EL, Mosher DF. Factor XIIIa-mediated crosslinking of fibronectin in fibroblast cell layers. Crosslinking of cellular and plasma fibronectin and of amino-terminal fibronectin fragments. J Biol Chem 1989; 264: 4179-4185.
    PubMedGoogle Scholar
  • 69 Sane DC, Moser TL, Pippen AM. et al. Vitronectin is a substrate for transglutaminases. Biochem Biophys Res Commun 1988; 157: 115-120.
    CrossrefPubMedGoogle Scholar
  • 70 Ueyama M, Urayama T. The role of factor XIII in fibroblastproliferation. Jpn J Exp Med 1978; 48: 135-142.
    PubMedGoogle Scholar
  • 71 Bruhn HD, Pohl J. Growth regulation of fibroblasts by thrombin, factor XIII and fibronectin. Klin Wochenschr 1981; 59: 145-146.
    CrossrefPubMedGoogle Scholar
  • 72 Brown LF, Lanir N, McDonagh J. et al. Fibroblast migration in fibringel matrices. Am J Pathol 1993; 142: 273-283.
    PubMedGoogle Scholar
  • 73 Zamboni P, De Mattei M, Ongaro A. et al. Factor XIII contrasts the effects of metalloproteinases in human dermal fibroblast cultured cells. Vasc Endovascular Surg 2004; 38: 431-438.
    CrossrefPubMedGoogle Scholar
  • 74 Herouy Y, May AE, Pornschelegel G. et al. Lipodermatosclerosis is characterized by elevated expression and activation of matrix metalloproteinases: Implications for venous ulcer formation. J Invest Dermatol 1998; 111: 822-827.
    CrossrefPubMedGoogle Scholar
  • 75 Norgauer J, Mockenhaupt M, Herouy Y. Blood coagulation factor XIII and wound healing in leg ulcers. Biochem Prog 2001; 14: 67-70.
    PubMedGoogle Scholar
  • 76 Anwar R, Gallivan L, Edmonds SD. et al. Genotype/phenotype correlations for coagulation factor XIII: specific normal polymorphisms are associated with high or lowfactor XIII specificactivity. Blood 1999; 93: 897-905.
    PubMedGoogle Scholar
  • 77 de Lange M, Andrew T, Snieder H. et al. Joint linkage and association of six single-nucleotide polymorphisms in the factor XIII-A subunit gene point to V34L as the main functional locus. Arterioscler Thromb Vasc Biol 2006; 26: 1914-1919.
    CrossrefPubMedGoogle Scholar
  • 78 Stacey MC, Burnand KG, Layer GT, Pattison M, Browse NL. Measurement of the healing of venous ulcers. Aust N Z J Surg 1991; 61: 844-848.
    CrossrefPubMedGoogle Scholar
  • 79 Dardik R, Solomon A, Loscalzo J. et al. Novel proangiogenic effect of factor XIII associated with suppression of thrombospondin 1 expression. Arterioscler Thromb Vasc Biol 2003; 23: 1472-1477.
    CrossrefPubMedGoogle Scholar
  • 80 Dardik R, Loscalzo J, Inbal A. Factor XIII (FXIII) and angiogenesis. J Thromb Haemost 2006; 1: 19-25.
    PubMedGoogle Scholar
  • 81 Nahrendorf M, Hu K, Frantz S. et al. Factor XIII deficiency causes cardiac rupture, impairs wound healing, and aggravates cardiac remodeling in mice with myocardial in farction. Circulation 2006; 113: 1196-1202.
    CrossrefPubMedGoogle Scholar
  • 82 Dardik R. et al. Evaluation of the pro-angiogenic effect of factor XIII in heterotopic mouse heart allografts and FXIII-deficient mice. Thromb Haemost 2006; 95: 546-550.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 83 Gemmati D, Federici F, Campo G. et al. Factor XIIIA-V34L and factor XIIIB-H95R gene variants: effects on survival in myocardial infarction patients. Mol Med 2007; 13: 112-120.
    PubMedGoogle Scholar
  • 84 New and emerging theories of cardio vascular disease: infection and elevated iron. Biol Res Nurs 2004; 6: 3-10.
    CrossrefPubMedGoogle Scholar
  • 85 Kervinen H, Tenkanen L, Palosuo T. et al. Serum iron, infection and inflammation; effects on coronary risk. Scand Cardiovasc J 2004; 38: 345-348.
    CrossrefPubMedGoogle Scholar
  • 86 Levine SM, Chakrabarty A. Therole of iron in the pathogenesis of experimental allergic encephalomyelitis and multiple sclerosis. Ann NY Acad Sci 2004; 1012: 252-266.
    CrossrefPubMedGoogle Scholar